Dr. M.Moshfeghi OBS&GYN - PowerPoint Presentation

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Dr.

M.Moshfeghi

OBS&GYN

fellowship of

perinatology

RUYAN INSTITUTE

ROLE OF PROGESTERONE IN

PREGNANCY MAINTENANCE

&

LATER

IN

PREGNANCY

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Preterm birth

refers to a delivery that occurs before 37 0/7ths

refers to a delivery that occurs before 37

0/7ths

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The percentage of newborns delivered at very low

birthweight

has declined only minimally1.46 percent in 2008

1.45 percent

in 2010

preterm birth continues to be a major determinant of short- and long-term morbidity in infants and children has declined only minimally1.46 percent in 2008 1.45 percent in 2010 major determinant of short- and long-term morbidity in infants and children

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pathophysiologic

events occurring with

mother, placental

fetal compartment

.

Therefore,

functional progesterone withdrawal failure of transformation of the spiral arteriesfetal stress due to uteroplacental vascular insufficiencyfunctional progesterone withdrawal

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true

labor (contractions

result

in cervical change)

from

false labor (contractions that do not result in cervical change).challenge of distinguishing

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Transvaginal

ultrasound

Is

the most reliable method for measuring cervical length.

In symptomatic

and asymptomatic preterm patients,

a short cervix (<30 mm) is predictive .the most reliable method for measuring cervical lengthIn symptomatic and asymptomatic preterm patients,

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Progesterone supplementation to reduce the risk of spontaneous preterm birth

ROLE OF PROGESTERONE IN PREGNANCY MAINTENANCE

EFFICACY OF PROGESTERONE FOR PREVENTION OF PRETERM BIRTH

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Preterm birth

complicates

1 in 8 over 85 percent of all perinatal

morbidity and mortality.

Efforts to delay delivery

have been largely unsuccessful. much attention has focused on preventative strategies.Efforts to delay delivery have been largely unsuccessful. much attention has focused on preventative strategies

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Sonographic

imaging

imaging of the cervix across gestation has enhanced our understanding of cervical performance

Cervical effacement is one of the first steps in the parturition process,

preceding labor by at least four to eight weeks.

Cervical effacement is one of the first steps in the parturition process, preceding labor by at least four to eight weeks.

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Sonographic

imaging

Effacement begins at the internal cervical os

and proceeds caudally,

.

,

it can be seen by ultrasound, but is NOT by digital or visual examination

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.

Transabdominal

images of the cervix are

less

reproducible;

thus, they should

not be used for clinical management

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Timing

  CL

before 14

weeks have limited clinical value .

However,

high-risk pregnancies, prior second trimester losses and/or large (or multiple) cone biopsies, cervical shortening has been seen as early as 10 to 13 weeksReproducible measurement of at about 14 weeks, when the cervix normally becomes distinct from the lower uterine segment.high-risk pregnancies, prior second trimester losses and/or large (or multiple) cone biopsies, cervical shortening has been seen as early as 10 to 13 weeks

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With proper technique,

the intra- and inter-observer

variabilities are

<10 percent

.

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Cervical length is

stable between 14 - 28 weeks

,

declines

substantially after 28 to 32 weeks. stable between 14 - 28 weeksafter 28 to 32 weeks.

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Between about

14 and 28 weeks

, the length of the cervix is described by a normal bell-shaped curve :

2nd

centile

at 15 mm

5th centile at 20 mm 10th centile at 25 mm 50th centile at 35 mm 90th centile at 45 mm Between about 14 and 28 weeks

, the length of the cervix is described by a normal

bell-shaped curve

:

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t

he median cervical length is

40 mm before 22 weeks, 35 mm at 22 to 32 weeks,

30 mm after 32 weeks

.

Cervical length is not significantly affected by parity, race/ethnicity, or maternal height

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The significance of differences

in

the rate of cervical change

(

eg

, 30 mm to 20 mm Versus 20 mm to 15 mm over two weeks) for prediction of preterm birth is unclear,

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ROLE OF PROGESTERONE IN PREGNANCY MAINTENANCE

 —

 

Progesterone initially produced by

the corpus

luteum

. is critical for the maintenance of early pregnancy the placenta takes over this function at 7 to 9 weeks removal of the source of progesterone (the corpus aluteum) or administration of a progesterone receptor antagonist induces abortion before 7 weeks (49 days) of gestation.

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The role of progesterone later in pregnancy

,

less clear.

maintaining uterine quiescence

, the onset of labor both at term and preterm is associated with

a

functional withdrawal of progesterone activity at the level of the uterusa functional withdrawal of progesterone activity at the level of the uterus, less clear. maintaining uterine quiescence

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The role of progesterone later in pregnancy

Progesterone has been shown to

prevent apoptosis in

fetal membrane

explants, under both basal

Prevent pro-inflammatory conditions may help to prevent preterm premature rupture of membranes (PPROM), prevent apoptosis in fetal membranePrevent

pro-inflammatory

conditions

may help to prevent

preterm premature rupture of membranes (PPROM

),

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EFFICACY OF PROGESTERONE FOR PREVENTION OF PRETERM BIRTH

 

depends primarily on

appropriate patient selection

reduces the risk of preterm birth by one-third

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Progesterone supplementation?

YES

Hydroxyprogesterone

caproate

250 mg IM weekly beginning between 16 and 20 w and continuing through 36 w of gestation or until delivery and monitor cervical length. Short (<25 mm) cervix → perform cerclageSingleton pregnancy, prior spontaneous singleton preterm birth, normal cervical length

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Progesterone supplementation indicated?

Possibly

Hydroxyprogesterone

caproate

250 mg weekly beginning 16 and 20 weeks through 36 weeks or until delivery

and monitor cervical length. Short (<25 mm) cervix → perform cerclageSingleton pregnancy, prior spontaneous twin preterm birth, normal cervical length

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Progesterone supplementation indicated?

Yes

Singleton pregnancy,

no prior spontaneous preterm birth,

short cervix (≤20 mm)

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Progesterone suppository 90 to 200 mg

vaginally each night from time of diagnosis through 36 weeks.

a 100 mg micronized progesterone vaginal tablet

an 8 percent vaginal gel containing 90 mg

micronized progesterone per dose.

Both preparations are commercially available in US, but not approved for prevention of preterm birth in cervical shortening.

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Multiple pregnancy

(twins or triplets)

without prior preterm birth, normal cervical length

No

No progesterone,

no

cerclage

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Twins,

prior preterm birth

Possibly

Hydroxyprogesterone

caproate 250 mg IM weekly beginning between 16 and 20 weeks of gestation and continuing through 36 weeks of gestation or until delivery.

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Twins,

short cervix

Possibly

Vaginal progesterone,

no

cerclage

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Twin pregnancy

the efficacy of high dose vaginal progesterone (

400 mg/day

)

no more effective

than lower dose therapy (200 mg/day) or a placebo,

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YES

We suggest 17P supplementation for women with a singleton pregnancy who have had a prior preterm birth, singleton or twin.

Spontaneous twin preterm birth in prior pregnancy

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No

Preterm premature rupture of membranes No

Positive fetal

fibronectin

test No

Undelivered after an episode of pretermlabor No

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By monitoring with an external

tocodynamometer

once a week for 60 min,

significant difference

in the frequency of spontaneous uterine contractions between the two groups,

SO

progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy.significant difference progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy

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if all

eligible women had received progesterone prophylaxis,

it

would only have reduced the overall preterm birth rate in the United States by

approximately 2 percent

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after placement of a

cerclage

Cerclage

 —

 a prior preterm birth,

continuing 17P supplementation

has not been proven to be useful,?????????

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women with a history of preterm birth due to PPROM

YES

,

appear to

benefit from progesterone supplementation

in subsequent pregnancies

;

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Acute preterm labor

 .

do not routinely recommend progesterone

supplementation in this setting

.

NONO

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Uterine anomaly or ART

NO

 — 

There

are no data

on the effectiveness of progesterone therapy for prevention of preterm birth in uterine malformations OR who conceive with assisted reproductive technologyNO

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SIDE EFFECTS AND ADVERSE EFFECTS

 

three-fold increase

in risk of developing gestational diabetes in some studies

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Progesterone exposed infants

less

perinatal

morbidity,

reduced rates of

necrotizing

enterocolitis, intraventricular hemorrhage, need for supplemental oxygen. There was no evidence of virilization of female offspring, which is a theoretic concern of this therapy

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Several studies have reported

a

nonstatistical increase in risk

of miscarriage and stillbirth

in pregnancies exposed to

progestins

but others could not confirm this observation or observed a nonstatistical decrease in these risks

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PROGESTERONE PREPARATIONS, ROUTES, AND DOSES

 

—

have

been effective

at reducing the risk of preterm birth compared with no treatment/placeboall formulations

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Evidence

is insufficient

to define the optimum gestational age

for starting treatment

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17-alpha-hydroxyprogesterone (17P)

 

natural progesterone metabolite made by the corpus

luteum

and placenta

minimal to no androgenic activity.

intramuscularly. 25 mg every five days to 1000 mg weekly, beginning as early as 16 weeks of gestation. We use a 250 mg dose17-alpha-hydroxyprogesterone (17P)

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.

Standard contraindications to progesterone administration include

hormone-sensitive cancer

, liver disease,

uncontrolled hypertension

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This is

the first time that

the FDA has approved a medication,

and

represents the first approval of a drug specifically

for use in pregnancy in more than 15 years

. for the prevention of preterm birth

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Natural

progesterone is typically administered vaginally.

high uterine bioavailability

since uterine exposure occurs before the first pass through the liver.

few systemic side effects

, but vaginal irritationneeds to be administered daily. Doses of 90 to 400 mg, beginning as early as 18 weeks of gestation. We use 100 mg administered vaginally each evening; however, in some areas a 200 mg suppository may be more readily available and less costlyVaginal progesterone preparations

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An

oral micronized preparation of natural progesterone also exists.

Daily doses of 900 to 1600 mg

have been given.

Reported side effects include

sleepiness, fatigue and headache Oral progesterone

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For women

with

a singleton pregnancy who have had a previous spontaneous singleton

PTL

suggest

intramuscular injections of 17-alpha- hydroxyprogesterone caproate rather than vaginal progesterone (16 to 20 weeks) and continuing through the 36 th weeka previous spontaneous singleton PTL

intramuscular injections of 17-alpha-

hydroxyprogesterone

caproate

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cervical

shortening (defined as ≤20 mm

before 24 weeks) and no prior spontaneous singleton preterm birth,

suggest

vaginal

progesterone

through the 36 th week. vaginal suppository (100 or 200 mg), gel (90 mg), or tablet (100 mg micronized progesterone)vaginal progesterone

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Use of progesterone for indications

other

than

is

not supported

prior preterm birth

and short cervix

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Progestational

Agents to Prevent Preterm Birth. Progesterone

supplementation for women at risk for preterm birth was

investigated with regard to several plausible mechanisms of

action, including reduced gap junction formation and

oxytocin

antagonism leading to relaxation of smooth muscle, maintenanceof cervical integrity, and anti-inflammatory effects.

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Although the benefit of progesterone supplementation has

been observed in multiple research trials, the optimal clinical

protocols for progesterone have not yet been developed